Where the money goes

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Children's Cancer

Targeting cancer cell metabolism as a viable treatment strategy: new in vitro models are required

Cancer cells are now known to require functional mitochondria to survive. Many currently prescribed drugs show mitochondrial toxicities with a small number being currently tested in clinical trials as anti-cancer treatments . We have demonstrated that the artificial conditions researchers uses to grow cancer cell lines in the laboratory can dramatically affect how cancer cells respond to such agents. The effects of some drugs can be enhanced while others are reduced. What is required is an in vitro system which gives the researcher more control over the environmental components. Energy substrates including glucose and glutamine, pH and oxygen levels are vitally important to control if the situation in the patient tumour is to be modelled in the laboratory. In collaboration with a South Korean group we have developed a 3D perfusion system which allows cancer cells to be grown on a 3D scaffold to mimic the situation in a solid tumour. The cells can be perfused with a constant stream of physiological nutrients at a defined oxygen concentration. Different concentrations of drugs can be applied to the cells and cells monitored for changes in cell proliferation and cell death. Testing on a new prototype will commence in the Jan 2016 and funding is required to support this work.

Our Researchers

Dr Helen Townley, BSc, PhD
I am the William Dodd foundation Research Fellow, and lead a research group working on new and innovative therapies for childhood cancers.

My degree and PhD are in Biochemistry, and I have worked at the University of Oxford since 1998. I am now a University Research Lecturer, and a Senior Visiting Research Fellow in Engineering Sciences.

The fact that our research is supported by both the medical faculty and Engineering Sciences means that we are able to carry out interdisciplinary research ranging from nanoparticle synthesis and analysis through to cell culture and biological assays of materials.

My laboratory is based at the Begbroke Science Park in the Institute for Advanced Technology.

Karl Morten PhD, Principle Investigator,A leading international mitochondrial researcher with extensive research experience developed at the University of Oxford and the Buck Institute for Aging Research (California). Career highlights include identifying novel mutations in mitochondrial disease, the utility of using dichloroacetate to increase the activity of pyruvate mutations, identification of high levels of tau phosphorylation in the SOD2 mutant mouse brain. This experience has established Dr Morten as one of the leading mitochondrial research experts in Europe. PI at University of Oxford since 2010 investigating the role of the mitochondria in diabetes, cancer, drug toxicity, neuronal drug action and ischaemia,

Dr. Morten is driving mitochondrial research at the University of Oxford where the Morten laboratory is at the hub of a mitochondrial research. In addition to establishing a collaborative mitochondrial biology research community through the founding and contented co-ordination of MitOX; an Oxford-based international meeting on mitochondrial biology and metabolism Dr. Morten also sits on the University of Oxford metabolism committee. Dr. Morten’s international reputation in mitochondrial research has led to interest from the pharmaceutical sector with current projects running with Bayer, Glaxo Smithkline and GW Pharmaceuticals.

What they do

Re-purposing existing drugs to treat cancerMorten Research Group, University of Oxford, John Radcliffe Hospital.

With many cancers effectively treating malignant disease remains a major problem. Our research approach currently differs from that favoured by many other researchers and pharmaceutical companies. Rather than identifying a new drug-able target in the hope this will allow the development of a specific treatment which can target the cancer we are exploring the use of existing medications which have minimal side effects but show anti-cancer properties. Although potentially not eliminating the cancer completely, our hope is that this approach will reduce disease burden with minimal side effects and can be used in combination with other therapies (i.e radiotherapy).With many drugs in clinical use having off target effects in other organs the possibility that existing medications could be beneficial in other conditions is an area explored by the pharmaceutical sector. Asprin is a good example. Initially used in the treatment of headache Asprin is now used as an anti-coagulant following stroke and shows potential in treating bowel cancer. In the Morten group we are investigating whether drugs which target mitochondrial energy production have the potential to i) reduce general cancer growth and ii) improve the efficacy of chemotherapy agents in drug resistant cancers.

Recent discoveries in cancer biology which show a greater level of versatility in how cancer cells generate their energy and obtain nutrients has emphasised the potential importance of mitochondria to cancer cell growth. Unwanted mitochondrial toxicity is a problem for the Pharmaceutical industry with many therapeutic agents causing significant mitochondrial toxicity. If the effects are subtle this may not be identified during research and development with the effects only observed when drugs are used on human subjects. If toxicity is significant the drugs are withdrawn from the market leading to losses of billions of £’s in drug development costs. If the only effective treatment for a condition low levels of mitochondrial toxicity, are tolerated by the drug administration agencies with drugs being given Black Box safety warnings. Several drugs with known mitochondrial effects show signs of reducing the likelihood of cancer developing in patients undergoing prolonged treatment. The blood glucose lowering drug metformin which is hypothesised to work by inhibiting mitochondrial function in the liver/muscle appears to reduce the incidence of cancer in diabetics taking the drug compared to those on other treatments.

We have generated exciting preliminary data which suggests that targeting mitochondria with relatively non-toxic drugs (i.e. Meclizine and Bithionol) can reduce cancer cell growth with increased levels of cell death. Using the drug phenformin we have shown that attenuating mitochondrial function in chemotherapy resistant cell lines can increase the effectiveness of chemotherapy agents. Carryout out experiments under physiological concentrations of glucose (1-5mM) has been crucial in identifying these anti-cancer effects. If the high concentrations of glucose (25mM) used by most cancer researchers are used the potency of our drugs is markedly reduced. Our future studies will further model our system to reflect the situation in tumours in patients by regulating levels of oxygen as well as glucose. A 3D system where cancer cells are being perfused has also been developed which allows us to carryout long term experiments under low glucose conditions with different drug concentrations.

Science

Helen Townley, Oxford University

Better cancer treatment regimens rely on the identification or synthesis of new active compounds, and their effective delivery to tumour sites.

The richest source of novel compound classes for biological and pharmaceutical studies are natural products. In fact, approximately 25% of drugs in the modern pharmacopoeia are derived from plants, and many others are synthetic analogues built on prototype compounds isolated from plants. As such, up to 60% of prescribed drugs in the Western World contain plant products or their derivatives. These compounds have wide structural and functional diversity, biochemical specificity and desirable molecular properties. Natural compounds are classed as ‘privileged structures’ meaning that they have evolved over millennia as a result of evolutionary pressure and therefore possess specific biological activity, rather than randomly assembled synthetic chemicals. At present we are screening libraries of plant extracts and assessing their activity against Rhabdomyosarcoma cells (one of the most common solid tumours in children)

Furthermore, we aim to capitalize on our expertise in nanoparticles synthesis, as a means of drug delivery, protection of the compound from degradation, and for co-delivery of drugs in a defined ratio. Combination therapy is a powerful and effective therapeutic regimen in the treatment of cancers, which can generate increased efficacy and reduced side effects, leading to optimal therapeutic outcomes. The ability to identify the ratio of drugs that will produce a synergistic benefit, and a technology that makes it possible to maintain and deliver that ratio in the body, could have a profound impact on combination chemotherapy efficacy.

It is not sufficient to assume that therapies for adults can simply be translated to paediatric cancers. Adults and children are known to have different tolerance and response to treatments.
Cancer still remains the leading cause of death in children.

Mission Statement

William's Fund is a fundraising organisation raising money for Childhood Cancer Research in Oxford. We are part of the Oxford Radcliffe Hospitals Charitable Funds Registered charity no. 1057295 (Fund 0085). There are no administration costs (covered by us). We do not have any paid employees!